Caloric restriction (CR: reducing caloric intake 30-40 percent below ad libitum levels) remains the only intervention that reproducibly extends lifespan, reduces the incidence and delays the onset of age-related disease, enhances stress protection, and attenuates functional decline in mammals. Although the effects of CR on aging have been widely reported in rodents and other short-lived species, its application to a primate model is relatively new and still unproven. In 1987, the National Institute on Aging began the first well controlled long-term study in a species with a considerably longer lifespan and a closer physiology to humans. Monkeys benefit from CR with a lower body weight, body fat, and blood glucose and thus are at lower risk for developing diabetes and heart disease. Changes in several endocrine measures indicate an altered hormonal axis. Despite the caloric deficit, female monkeys are not reproductively compromised and both males and females may benefit immunologically. [unreadable] We are actively developing a behavior program to test learning, memory, motor function, and activity. Tests of delayed responses taxing short-term memory are the best characterized in aging monkeys. Performance in tasks such as object discrimination and object reversal were age-sensitive, but there were no significant differences in performance between diet groups. The lack of diet effects in the object discrimination tasks is important for reducing concerns about diet effects on noncognitive performance factors. An automated touch screen system is in development which will be used to test even more complex tasks. Moreover, further analyses are ongoing including correlating behavioral function with in vivo brain imaging. Age-related declines in the volume of the striatum as well as reduced binding potential of dopamine D2 receptors have been documented. Additionally, we are studying a test of motor performance that measures reaction time, coarse, and fine motor movement. For both young and old age groups, fine motor performance was equivalent between diet groups on the simple tasks, but on the more difficult task, retrieval time was significantly faster for the CR monkeys. [unreadable] We continue to monitor morbidity and mortality, but the number of deaths and diagnosed diseases remains too low for conclusive statistical analyses. [unreadable] [unreadable] Two additional studies of age-related disease focus on cardiovascular disease and dietary interventions. These studies are being conducted in collaboration with the Laboratory of Cardiovascular Science (LCS). Although there is considerable evidence linking salt intake to hypertension, how this dietary variable is involved in remodeling of the vascular wall to affect arterial stiffness is still unknown. The effect of an incrementally increased salt load on vascular stiffness and modulation of this response by production of an endogenous ligand, marinobufagenin, has been studied in nine old normotensive male rhesus monkeys. Sodium excretion significantly increased with each incremental increase in dietary intake. Arterial stiffness increased as a direct nonlinear function of sodium intake independent of changes in blood pressure. These results suggest that old monkeys are susceptible to sodium dependent vascular changes that can be partially compensated by increases in naturally occurring ligands which enhances sodium excretion. Additional analysis of the tissue and serum is underway.[unreadable] A second study in progress consists of monkeys over a broad age range eating either a diet moderately high in cholesterol or a low cholesterol control diet. The aims of this study are threefold: 1) To demonstrate links between the vascular changes present with aging and the early development and progression of atherosclerotic lesions; 2) To determine plasma biochemical markers which correlate with age-related vascular remodeling and atherogenesis; and 3) To validate the value of contrast enhanced-magnetic resonance imaging as a noninvasive diagnosis of atherosclerosis. Preliminary data indicate that arterial stiffness increased prior to changes in blood pressure and that old monkeys had more severe atherosclerotic lesions than younger monkeys.